A series of substituted derivatives containing the 1,4-benzodioxine or pyrrole nucleus are described. All the newly synthesized compounds were examined for their in vitro and in vivo anti-inflammatory activity. Several derivatives, including (S)-2, 14 and 17, showed more anti-inflammatory activity in vivo in these assays (rat paw oedema induced by carrageenan) than the known classical anti-inflammatory agent ibuprofen, whereas other compounds like 1 were equipotent to ibuprofen. Compound 17 was the most outstanding derivative because of its remarkable in vivo anti-inflammatory activity. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

The diazonium salt derived from 4-amino-N,1,3-trimethyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-pyrazole-5-carboxamide (14) was reacted with a mixture of CuSO4 and NaCl, with ascorbic acid as an initiator to afford the planar derivative 4,6-dihydro-1,4,6,8-tetramethyl-3-phenyldipyrazolo[3,4-b:4′,3′-d]pyridin-5(3H)-one (16) and its unexpected isomer 4,6-dihydro-3,4,6,8-tetramethyl-1-phenyldipyrazolo[4,3-b:4′,3′-d]pyridin-5(1H)-one (17), as well as the epimers (3S,4S)- (or (3S,4R)-) and (3S,4R)- (or (3S,4S)-) 4-chloro-2,4-dihydro-1′,3′,5,5′-tetramethyl-2-phenylspiro[pyrazole-3,4′(1′H)-pyrrolo[3,4-c]pyrazol]-6′(5′H)-one (18a and b, respectively). Epimers 18a and b were converted under basic conditions to 4′-chloro-N,1,3,3′-tetramethyl-1′-phenyl-[4,5′-bi-1H-pyrazole]-5-carboxamide (19). The structures of isomers 16 and 17 determined by single-crystal X-ray analysis are also reported. Linear dichroism (LD) measurements for the above isomers suggest that 17 intercalates into DNA, and 17 exhibited antiproliferation activity against human NCI-H460 pulmonary carcinoma cells.

Derivatives of the title ring system of type 10 were obtained in good yield by fusion of the intermediates 12. Attempt to cyclize the acetylamino derivative 9 under Bischler-Napieralski conditions failed because of the insufficient electronic density in the position 4 of the pyrazole ring created by the adjacent carbonyl moiety.The derivatives of the new ring system, assayed as anxiolytic agents, showed no significant activity.

In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 mug ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with air IC50 value of 5.8 versus 3.2 muM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC50 values of 0.34 and 1.0 muM, respectively. At 10 muM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 muM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly. (C) 2004 Elsevier SAS. All rights reserved.

Several new ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates 2, substituted at 2 and, alternatively at, 6, 7 or 8 positions of the quinazolinone nucleus, were synthesised. The compounds were screened for their analgesic and antiinflammatory activities, acute toxicity and ulcerogenic effect. Substitution in the benzene moiety of the quinazolinone ring did not show any advantage for the analgesic activity, whereas it improved in some cases the antiinflammatory activity. Some compounds showed appreciable antiinflammatory activity and, at the same time, very low ulcerogenic index.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.

The diazonium salts obtained from 2-amino-N-methyl-N-(1-phenyl-3-methylpyrazol-5-yl)benzamide were reacted with cuprous oxide or copper at 5 or 25 degrees C under different pH conditions. Cuprous oxide at 25 degrees C and pH 6.25 yielded the racemic epimers (3'SR,4'RS)-and (3'SR,4'SR)-4'-hydroxy-2',4'-dihydro-2,5 dimethyl-2'-phenylspiro[isoindoline-1,3'-3'H-pyrazol]-3-ones 2 and 10 respectively, (RS)-2',4'-dihydro-2,5'-dimethyl-2'-phenylspiro[isoindoline 9 and N-methylphthalimide 8, The thermal transformation of 2 and 10 into the potentially pharmacologically active 3-methyl-1-phenyl[2]benzopyrano[4,3-c]pyrazol-5(1H) 4 was strongly dependent on the structure of the two epimers, When I was reacted with cuprous oxide or copper sulfate and sodium halide (chloride or bromide), in the presence of ascorbic acid as initiator, a mixture of epimers (3'SR,4'RS)- and (3'SR,4'SR)-4'-chloro(or bromo)-2',4'-dihydro-2,5'-dimethyl-2'-phenylspiro[isoindoline-1,3'-3' H-pyrazol]-3-ones 6b and 7b (or 6c and 7c) was obtained. The same epimers were obtained when the diazonium halides (chloride and bromide) 1b,c obtained from 2-amino-N-methyl-N-(1-phenyl-3-methyl-1H-pyrazol-5-yl)benzamide were treated with the appropriate classical Sandmeyer catalysts. The formation of the spiro compounds is based on consecutive Pschorr and Sandmeyer reactions. The X-ray crystal structures of the epimers 2 and 10 have been determined, confirming the given formulations.

Several new 4-diazopyrazole derivatives were synthesized by reaction of 1-(R-substituted)phenyl-3-methyl-5-benzamidopyrazoles with a sevenfold excess of nitrous acid in acetic media. The compounds were tested at 20 microM concentration for their antineoplastic activity in vitro against Raji (human Burkitt lymphoma), K562 (human chronic myelogenous leukemia) and U937 (human histiocytic lymphoma) cell lines. They showed a percent of growth inhibition in the range 23.4-100%.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A number of new 4-diazopyrazole derivatives were prepared by the reaction of 1-R-3-methyl-5(R(1)-substituted)benzamidopyrazoles with a sevenfold excess of nitrous acid in acetic medium. The compounds were tested for activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, Listeria monocytogenes, Candida albicans, Candida tropicalis and Paecilomyces varioti. The highest microbial susceptibility was shown by Gram-positive bacteria, with minimum inhibitory concentrations (MIG) in the range 0.5-12.5 mu g/mL. For S aureus the R(1) substituents were screened utilizing the Topliss operational scheme. The 4-nitro group was found to be the best substituent. We also tested the compounds 4l,o,p, found to be the most active in the test against S aureus ATCC 25923, on ten clinical S aureus strains, five of which were sensitive and five resistant to methicillin. The above compounds were active in the range 2-8 mu g/mL against methicillin-resistant S aureus strains. An X-ray analysis of compounds 4i and 4q is reported.

A number of new 3-(indazol-3 and 5-yl)-4(3H)-quinazolinone and 4(3H)-benzotriazinone derivatives were prepared by reaction of 3- or 5-(2-aminobenzamido)indazole with ethyl orthoesters and nitrous acid respectively. Structures were established on the basis of analytical and spectroscopic data. Single-crystal X-ray analysis confirmed the quinazolinone structure of compounds (5). The 4(3H)-quinazolinones and 4(3H)-benzotriazinones were tested at 200 mu g/ml for antimicrobial activity against C. albicans, C. tropicalis and S. aureus, at 100 mu M for their antitumor effect on human-lymphoblast-like cells and finally at 500 mu M for 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) inhibition.

8,9-Dihydrodipyrazolo[3,4-b:4',3'-f][1,5]diazocin-10(1H)-ones 7 were prepared by cyclization of 1-ethyl-N,3-dimethyl-4-acetamido-N-(1-R(1)-3-R(2)-1H-pyrazol-5-yl)-1H-pyrazole-5-carboxamides 6 by a Bischler-Napieralski cyclization. A complete assignment of the chemical shifts to the carbon atoms of compound 7 was performed by different nmr experiments, such as DEFT and XHDEPT for one-bond C-H correlations and COLOC experiments for long-range C-H correlations.

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Some carboxylic acids of N(3)-pyrazole substituted 1,2,3-benzotriazin-4-(3H)-ones and- quinazolin-4-(3H)-ones were prepared and tested for the inhibitory property of 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol. The results indicated that the degree of inhibition can be used to predict the antiinflammatory potency of the compounds described.

A number of new ethyl 1-methyl-5-[4-oxo-3(4H)-quinazolinyl]-1H-pyrazole-4-acetates substituted at the 2 position of the quinazolinone ring were prepared. The compounds were tested for analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effect. The 2-methyl, 2-ethyl and 2-phenyl derivatives proved to be more active than acetylsalicylic acid and phenylbutazone in the phenylbenzoquinone writhing test. The 2-methyl derivative was also as active as acetylsalicylic acid in the carrageenin paw oedema test. All the compounds showed very reduced ulcerogenic effects and systemic toxicity.

The Pschorr reaction performed under non-classical reaction conditions on the diazonium chloride derived from 2-amino-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)benzamide 1 afforded the epimers (3'R,4'S)- and (3'R,4'R)-4'-chloro-2',4'-dihydro-2,5'-dimethyl-2'-phenylspiro[isoindoline-1,3'-3'H-pyrazol]-3-one 4a and 4b together with the related enantiomers. The epimers were easily converted under acid conditions into both 4-chloro-3-methyl-5-[2-(methylcarbamoyl)phenyl]-1-phenyl-1H-pyrazole 5 and the potentially pharmacologically active 3-methyl-1-phenyl-1H-[2]benzopyrano[4,3-c]pyrazol-5-one 3, whereas under base conditions, as well as thermally, only compound 5 was obtained.The molecular structure of epimer 4a and that of the derivative 5 were confirmed by single-crystal X-ray analysis. The crystal of compound 5 is characterized by the presence of two conformational isomers in the unit cell.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Some N-(pyrazol-5-yl)-2-nitrobenzamides, variably substituted in the pyrazole nucleus as well as in the amidic group, were reacted in acetic acid media with potassium nitrite and hydrochloric acid. The different chemical behaviour of the reacted pyrazole derivatives in relation to the substitution pattern in both the pyrazole nucleus and the amidic group, was observed. All compounds isolated from the reaction mixtures (4-nitroso, 4-nitro, 4-diazo and 4-chloro derivatives) were evaluated by the agar diffusion method for their "in vitro" growth inhibitory activity against Candida albicans (our collection), Candida tropicalis ATCC 13803, Saccharomyces cerevisiae ATCC 36375, Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The 1-methylpyrazole derivatives showed larger inhibition zones than the 1-phenyl ones in the antimicrobial tests.